Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro.

Abstract

To determine the effects of immunomodulatory agents upon HIV replication in macrophages, cultured monocyte-derived macrophages were treated with various substances and then infected with a macrophage-tropic strain of HIV-1. Pretreatment with rIFN-alpha, IFN-beta, and IFN-gamma, or bacterial LPS prevented viral replication in macrophages. In treated cultures, little or no infectious HIV or p24 core antigen was released into the supernatant, no virions were seen by electron microscopy, no viral RNA or DNA was detectable in the cell lysates, and no cytopathology (as determined by multinucleated giant cell formation) occurred. In contrast, pretreatment with a wide dose range of recombinant IL-1 beta, IL-2, IL-4, IL-6, M-CSF, TNF, or lymphotoxin failed to protect macrophages from productive infection by HIV. A consistent effect of granulocyte/macrophage-CSF on HIV replication in macrophages was not observed. In dose response studies, pretreatment with approximately 100 U/ml of IFN-alpha, approximately 10 U/ml of IFN-beta, or approximately 100 U/ml of IFN-gamma was sufficient to prevent virion release maximally and to prevent cytopathology completely. In kinetic studies, IFN-alpha, IFN-gamma, or LPS were added to the macrophage cultures either before or after infection with HIV. Even when added 3 d after infection with a multiplicity of 1 50% tissue-culture infectious dose per cell, all three treatments markedly reduced virion release, suggesting that these agents act at a point in the viral life cycle beyond the early events of virus binding, penetration, and uncoating. These data indicate that HIV replication in previously uninfected macrophages may be regulated by an inducible host cell mechanism. These findings may explain the restricted replication of HIV in macrophages in vivo and suggest an antiviral role for interferons in the therapy of HIV infection.

Chemokine immunobiology in HIV-1 pathogenesis

“…Because data in this field are constantly being generated, Figure 2 should be considered as a helpful guide, but at best provisional and subject to confirmation. During innate responses, long-standing observations of LPS-mediated inhibition of HIV-1 infection of macrophages have been recently re-visited to show that the effect is due in part to high CC chemokine secretion after LPS stimulation [124,125]. These observations are in accordance with LPS's effect on the nuclear translocation of NF-B, which in turn can transactivate the RANTES promoter [126].…”

Differentiation of Monocytes to Macrophages Switches theMycobacterium tuberculosisEffect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein β Expression

“…The effect of differentiation may be due to the interaction of proinflammatory stimuli and the IFN system. The suppression of HIV-1 replication seen after LPS stimulation closely resembles the suppression seen after addition of IFNs (13). Type I IFN is required for the suppressive effects of LPS and TNF-␣ on macrophages (16,17), and IFN-␤ mRNA is induced after LPS stimulation (14).…”

“…The enhancement of HIV-1 replication also occurs in primary blood monocytes after infection with M. tuberculosis or stimulation with mycobacterial products (11,12). Surprisingly, when monocytes are differentiated to macrophages, TNF-␣, LPS, and infection with M. tuberculosis suppress viral replication and LTR function (13)(14)(15). The effect of differentiation may be due to the interaction of proinflammatory stimuli and the IFN system.…”

Macrophages and HIV-1: dangerous liaisons

“…IFN- and - have long been known to inhibit HIV-1 replication by suppressing reverse transcription and preventing transcription of the integrated provirus Kornbluth et al, 1989;Tissot and Mechti, 1995). IL-10 and TNF- have been shown to have different effects on HIV replication in macrophages depending on the experimental conditions.…”